This is a multi-center, non-randomized, concurrent controlled, multi-arm, Phase 1 interventional, open-label, biologic assignment-based umbrella study evaluating the feasibility, safety and preliminary efficacy of an escalating dose regimen of up to 2 doses of TSC-100 and TSC-101 in patients with AML, MDS, or ALL following HCT from a haploidentical donor, MMUD, or MUD
A multi-center, non-randomized, controlled, multi-arm, Phase 1 interventional, open label, biologic assignment-based umbrella study is planned to evaluate the feasibility, safety, and preliminary efficacy of repeated dose regimen of TSC-100 and TSC-101 (TSC-100 and TSC-101 is a genetically engineered, donor-derived T cell targeting HA-1 and HA-2 respectively) in patients with AML, MDS, or ALL following HCT from a haploidentical donor, MUD, or MMUD. The primary objective of this study is to investigate the safety of single and repeated dosing of TSC-100 and TSC-101 in HLA A\*02:01 positive patients undergoing haploidentical allogeneic peripheral blood hematopoietic cell transplantation and determine the optimally tolerated dose range. The primary endpoints are: (1) incidence of dose-limiting toxicities (DLTs), and (2) incidence of adverse events (AEs) and serious AEs (SAEs) of TSC-100 and TSC-101 combined with the standard of care (SOC) compared with the SOC alone at 2 years of follow-up. The study will also investigate the efficacy of TSC-100 and TSC-101 combined with the SOC compared with that of the SOC alone to treat the study population and assess the immunogenicity of TSC-100 and TSC-101. Depending on the HLA type and minor antigen positivity, patients will receive either TSC-100 or TSC-101 combined with the SOC or only SOC. TSC-100 or TSC-101 will be administered intravenously. Standard of care will include reduced intensity conditioning (RIC), hematopoietic cell infusion, and acute graft-versus-host disease (GvHD) prophylaxis. Patients will undergo one of the following RIC regimens, following standard institutional procedures: fludarabine+cyclophosphamide+total body irradiation, fludarabine+melphalan+/-total body irradiation, thiotepa+busulfan+fludarabine or flurdarabine+melphalan+thiotepa. In addition, patients may receive other supportive care measures and infectious prophylaxis as necessary, according to institutional guidelines or standards. Successive cohorts of patients in the treatment arms will be started according to an interval 3+3 (i3+3) dose escalation design. Once the RP2D is identified, up to 20 additional patients may be enrolled at the RP2D. Dose escalations to the next cohort of TSC-100 and TSC-101 will be considered after the safety review committee (SRC) establishes reasonable safety for all patients enrolled into the current cohort. The safety and necessity of repeat dosing will also be determined by the SRC. The safety data for all patients that received at least one dose of TSC-100 or TSC-101 in the treatment arms will be included in the safety assessment to proceed to the next dosing level and the dose escalation meeting will occur when the last patient in the cohort completes the 40-day DLT evaluation period. Depending on the number of DLTs observed, the range of patients that could be enrolled in the dose escalation stage of this i3+3 study is 35 to 300, including patients in the control arm.
Study Type
INTERVENTIONAL
Allocation
NON_RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Enrollment
75
City of Hope
Duarte, California, United States
RECRUITINGYale
New Haven, Connecticut, United States
RECRUITINGMemorial Healthcare System
Hollywood, Florida, United States
RECRUITINGNorthside Hospital
Atlanta, Georgia, United States
RECRUITINGJohn Hopkins University
Baltimore, Maryland, United States
RECRUITINGMass General Hospital
Boston, Massachusetts, United States
RECRUITINGKarmanos Cancer Institute
Detroit, Michigan, United States
RECRUITINGHackensack University Medical Center
Hackensack, New Jersey, United States
RECRUITINGColumbia University
New York, New York, United States
RECRUITINGMount Sinai
New York, New York, United States
RECRUITING...and 5 more locations
Occurrence of dose limiting toxicities
Number of DLTs observed in patients compared to the control arm
Time frame: two years
Occurrence of adverse events
Number of adverse events in patients compared to control arm
Time frame: two years
Comparison of disease free survival in patients versus the control arm
Disease-free survival in patients versus the control arm at 6 months, defined as the time from date of transplant to death or relapse/progression, whichever comes first. Participants alive and disease free will be censored at the last follow-up.
Time frame: 6 months
Comparison of disease free survival in patients versus the control arm
Disease-free survival in patients versus the control arm at 12 months, defined as the time from date of transplant to death or relapse/progression, whichever comes first. Participants alive and disease free will be censored at the last follow-up.
Time frame: 12 months
Disease-free survival in patients versus the control arm at 18 months, defined as the time from date of transplant to death or relapse/progression, whichever comes first. Participants alive and disease free will be censored at the last follow-up.
Disease-free survival at Month 18 defined as the time from date of transplant to death or relapse/progression, whichever comes first. Participants alive and disease free will be censored at the last follow-up.
Time frame: 18 months
Comparison of disease free survival in patients versus the control arm
Disease-free survival in patients versus the control arm at 24 months, defined as the time from date of transplant to death or relapse/progression, whichever comes first. Participants alive and disease free will be censored at the last follow-up.
Time frame: 24 months
Comparison of relapse rates between patients and control arm
Relapse rates in patients versus the control arm at 6 months. Relapse is defined by either morphological or cytogenetic evidence of acute leukemia or MDS consistent with pre-transplant features, or radiologic evidence of lymphoproliferative disorders, documented or not by biopsy.
Time frame: 6 months
Comparison of relapse rates between patients and control arm
Relapse rates in patients versus the control arm at 12 months. Relapse is defined by either morphological or cytogenetic evidence of acute leukemia or MDS consistent with pre-transplant features, or radiologic evidence of lymphoproliferative disorders, documented or not by biopsy.
Time frame: 12 months
Comparison of overall survival between patients and control arm
Overall survival between patients versus the control arm, defined as the time interval between the date of transplant and death from any cause. Surviving participants will be censored at the last follow up.
Time frame: Up to 2 years
Anti TSC-100 antibodies
Presence and concentration of anti TSC-100 antibodies.
Time frame: 2 years
Anti TSC-101 antibodies
Presence and concentration of anti TSC-101 antibodies.
Time frame: 2 years
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